We have previously demonstrated that lymphoid organs are the major reservoir in vivo of human immunodeficiency virus type 1 (HIV-1). In early stages of HIV disease, follicular hyperplasia is the predominant histopathologic abnormality seen in lymph nodes (LN). HIV viral particles are trapped efficiently in the follicular dendritic cell (FDC) network. Viral burden and virus expression in peripheral blood (PB) are low during this period. In early stage disease, viral burden and replication are higher (5- to 10-fold) in LN compared to PB. As HIV disease progresses, LN architecture is progressively disrupted and the most common histopathologic abnormalities are follicular involution and lymphocyte depletion. Coincident with FDC network disruption is a loss of viral trapping capacity in germinal centers, increases in viral burden, and replication in PB and LN. The increases in the PB compartment are relatively greater than in LN, thus leading to a decrease in the dichotomy in viral burden, and replication between PB and LN. The effect of standard antiretroviral therapy on HIV burden and expression has been evaluated by sampling PB and LT of patients before and 8 weeks after either remaining untreated, remaining on zidovudine (ZDV), initiating ZDV, or adding didanosine (ddI) to ZDV. In individuals who did not undergo a change in therapy, patterns of histopathology, viral trapping, viral burden, and viral replication remained remarkably constant between week 0 and week 8. In the group that added ddI to ZDV therapy, modest treatment effects (i.e., downregulation of viremia and of levels of virus replication in lymph nodes) were seen. Similar studies are underway or planned to evaluate possible treatment effects of ZDV in later-stage patients. These include studies of dinitrochlorobenzene (DNCB), an immunomodulator, in intermediate-to-late stage patients; and HIV Immunogen in early stage patients.